DESCRIPTION (From the Applicant's Abstract): Apoptosis has often been described as being synonymous with programmed cell death, implying that apoptosis is the program for cell death. We have recently identified an alternative, non-apoptotic program for cell death that we believe has broad implications in the fields of neurodegeneration, neural development, tumor metastasis, cancer chemotherapy, and the evolution of cell death programs. This alternative program, dubbed paraptosis, is a widespread program for cell death that fulfills none of the morphological or biochemical criteria for apoptosis arid is not inhibited by apoptosis inhibitors. In the current submission, we propose to evaluate the "proteogenomics" of paraptosis: first, we propose to use DNA microarrays to assess gene expression in paraptosis and to compare it to that in apoptosis. Second, we propose to evaluate the proteomics of paraptosis by performing 2-dimensional polyacrylamide gel electrophoresis followed by nanospray sequencing to identify paraptosis-specific proteolytic cleavage and other protein modifications. Finally, we propose to utilize the yeast 2-hybrid system to identify elements of the "paraptosome," i.e., the complex that initiates paraptosis and is analogous to the apoptosome. Because apoptosis inhibitors fail to inhibit paraptosis, and because paraptosis appears to occur in some neurodegenerative disease states, we believe that it will be important to characterize paraptosis biochemically and to develop inhibitors of this program.